There is thought to be over 75 million abusers of amphetamines (AMPHs) and cocaine worldwide. Unlike drugs such as heroin, alcohol or nicotine, there is no FDA-approved medication to facilitate the treatment of psychostimulant abuse. Several preclinical and clinical studies have provided data suggesting that naltrexone (NTX) may have potential for this indication. However, a review of the literature reveals conflicting findings that require resolutio. Several clinical studies have shown that genetic variation moderates the effects of a number of medications used to treat substance use disorders. A recent meta-analysis concluded that the OPRM1 A118G SNP (rs1799971) significantly moderates the treatment efficacy of NTX in treating alcohol abuse, increasing the treatment efficacy by over 2 fold among G-allele carriers (AG/GG). The proposed application would be the first to investigate the moderating effect of this genotype in the efficacy of NTX to treat stimulant abuse. More specifically, we propose investigating the interaction between NTX and intranasal (IN) methamphetamine (50mg/70kg). Participants who meet DSM-V criteria for moderate-to-severe stimulant use disorder will complete testing sessions where the abuse liability of IN methamphetamine (M-AMPH) is assessed following pretreatment with NTX (0, 25, 50 mg). Naltrexone's effects upon the abuse potential of IN M-AMPH will be assessed using self-report measurements of positive subjective effects and drug self- administration. Medication effects on these validated predictors of abuse will be compared between A118G A allele homozygotes (AA) and G-allele carriers (AG/GG; an anticipated 25% of the total sample), in order to assess genetic moderation of treatment outcome. The advantage of this approach is that it may help to define individuals in which the treatment exerts its greatest effects. As a secondary aim of the study we will simultaneously assess for possible moderating effects of several functionally relevant genetic variants to predict the how NTX alters the subjective and reinforcing effects of IN M-AMPH [ANKK1 (rs1800497); D?H (rs1611115); DRD2 (rs2283265); OPRM1 (rs6912029); SLC6A3 (rs28363170)]. This study therefore utilizes a focused approach to assess the influence of a genetic polymorphism whose influence has been substantiated by other investigations, and an exploratory approach to assess the individual and combined influence of several likely genetic moderators. Combined, the two studies in this proposal will contribute to the assessment of the clinical utility of NTX fr treating psychostimulant abuse, and may help identify gene x pharmacological interactions contributing to the personalization of treatment.